期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 290, 期 35, 页码 21713-21723出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M114.628255
关键词
androgen receptor; gene transcription; prostate cancer; transcriptional coactivator; ubiquitin-dependent protease
资金
- Research Program of Innovative Cell Biology by Innovative Technology
- Japan Society for the Promotion of Science KAKENHI Grant [24-5985]
- Grants-in-Aid for Scientific Research [15K18465] Funding Source: KAKEN
Background: The androgen receptor (AR) plays a key role in prostate cancer progression. Results: USP7 is required for binding of the AR to chromatin. Conclusion: USP7 is a novel AR co-regulator that mediates AR activity. Significance: Pharmacological inhibition of USP7 represents a compelling therapeutic strategy for the treatment of prostate cancer. The androgen receptor (AR), a nuclear receptor superfamily transcription factor, plays a key role in prostate cancer. AR signaling is the principal target for prostate cancer treatment, but current androgen-deprivation therapies cannot completely abolish AR signaling because of the heterogeneity of prostate cancers. Therefore, unraveling the mechanism of AR reactivation in androgen-depleted conditions can identify effective prostate cancer therapeutic targets. Increasing evidence indicates that AR activity is mediated by the interplay of modifying/demodifying enzymatic co-regulators. To better understand the mechanism of AR transcriptional activity regulation, we used antibodies against AR for affinity purification and identified the deubiquitinating enzyme ubiquitin-specific protease 7, USP7 as a novel AR co-regulator in prostate cancer cells. We showed that USP7 associates with AR in an androgen-dependent manner and mediates AR deubiquitination. Sequential ChIP assays indicated that USP7 forms a complex with AR on androgen-responsive elements of target genes upon stimulation with the androgen 5-dihydrotestosterone. Further investigation indicated that USP7 is necessary to facilitate androgen-activated AR binding to chromatin. Transcriptome profile analysis of USP7-knockdown LNCaP cells also revealed the essential role of USP7 in the expression of a subset of androgen-responsive genes. Hence, inhibition of USP7 represents a compelling therapeutic strategy for the treatment of prostate cancer.
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